Research Spotlight

Vasudevan, A., J. W. Choi, G. A. Feghali, A. Y. Kluger, S. R. Lander, K. M. Tecson, M. Sathyamoorthy, J. M. Schussler, R. C. Stoler, R. C. Vallabhan, C. E. Velasco, A. Yoon and P. A. McCullough (2019). “First and recurrent events after percutaneous coronary intervention: implications for survival analyses.” Scand Cardiovasc J Jul 25: 1-6. [Epub ahead of print].

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Objectives. Using composite endpoints and/or only first events in clinical research result in information loss and alternative statistical methods which incorporate recurrent event data exist. We compared information-loss under traditional analyses to alternative models. Design. We conducted a retrospective analysis of patients who underwent percutaneous coronary intervention (Jan2010-Dec2014) and constructed Cox models for a composite endpoint (readmission/death), a shared frailty model for recurrent events, and a joint frailty (JF) model to simultaneously account for recurrent and terminal events and evaluated the impact of heart failure (HF) on the outcome. Results. Among 4901 patients, 2047(41.8%) experienced a readmission or death within 1 year. Of those with recurrent events, 60% had >/=1 readmission and 6% had >4; a total of 121(2.5%) patients died during follow-up. The presence of HF conferred an adjusted Hazard ratio (HR) of 1.32 (95% CI: 1.18-1.47, p < .001) for the risk of composite endpoint (Cox model), 1.44 (95% CI: 1.36-1.52, p < .001) in the frailty model, and 1.34 (95% CI:1.22-1.46, p < .001) in the JF model. However, HF was not associated with death (HR 0.87, 95% CI: 0.52-1.48, p = .61) in the JF model. Conclusions. Using a composite endpoint and/or only the first event yields substantial loss of information, as many individuals endure >1 event. JF models reduce bias by simultaneously providing event-specific HRs for recurrent and terminal events.

Spitler, C. A., E. R. Row, W. E. Gardner, 2nd, R. E. Swafford, M. J. Hankins, P. J. Nowotarski and D. W. Kiner (2019). “Tranexamic Acid Use in Open Reduction and Internal Fixation of Fractures of the Pelvis, Acetabulum, and Proximal Femur: A Randomized Controlled Trial.” J Orthop Trauma 33(8): 371-376.

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OBJECTIVE: To assess the safety and efficacy of tranexamic acid (TXA) use in fractures of the pelvic ring, acetabulum, and proximal femur. DESIGN: Prospective, randomized controlled trial. SETTING: Single Level 1 trauma center. PATIENTS: Forty-seven patients were randomized to the study group, and 46 patients comprised the control group. INTERVENTION: The study group received 15 mg/kg IV TXA before incision and a second identical dose 3 hours after the initial dose. MAIN OUTCOME MEASUREMENTS: Transfusion rates and total blood loss (TBL) [via hemoglobin-dilution method and rates of venous thromboembolic events (VTEs)]. RESULTS: TBL was significantly higher in the control group (TXA = 952 mL, no TXA = 1325 mL, P = 0.028). The total transfusion rates between the TXA and control groups were not significantly different (TXA 1.51, no TXA = 1.17, P = 0.41). There were no significant differences between the TXA and control groups in inpatient VTE events (P = 0.57). CONCLUSION: The use of TXA in high-energy fractures of the pelvis, acetabulum, and femur significantly decreased calculated TBL but did not decrease overall transfusion rates. TXA did not increase the rate of VTE. Further study is warranted before making broad recommendations for the use of TXA in these fractures. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Spechler, S. J. (2019). “Eosinophilic esophagitis: novel concepts regarding pathogenesis and clinical manifestations.” J Gastroenterol Jul 24. [Epub ahead of print].

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This report explores two hypotheses regarding eosinophilic esophagitis (EoE): (1) that the use of proton pump inhibitors (PPIs) might contribute to the pathogenesis of EoE by preventing peptic digestion of food allergens, by increasing gastric mucosal permeability to enable gastric absorption of those undegraded food allergens, and by causing microbial dysbiosis, and (2) that EoE, like eosinophilic gastroenteritis, might have mucosal-predominant and muscle-predominant forms, and that the muscle-predominant form of EoE might cause a variety of esophageal motility disorders including achalasia.

Schiffmann, R., D. G. Bichet, E. Benjamin, X. Wu and R. Giugliani (2019). “The migalastat GLP-HEK assay is the gold standard for determining amenability in patients with Fabry disease.” Mol Genet Metab Rep 20: 1-2 100494.

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The pharmacological chaperone migalastat is indicated for the treatment of Fabry disease in patients with an amenable GLA variant. Amenability is determined by an in vitro, good laboratory practice (GLP)-validated assay using HEK293 cells (GLP-HEK assay) performed at a single, highly experienced, GLP-certified laboratory using rigorous standards and extensive analytical validation to limit inter-assay variability. The recent report by Oommen et al. entitled “Inter-assay variability influences migalastat amenability assessments among Fabry disease variants” showed, despite technical differences between a non-GLP-validated assay and the GLP-HEK assay, 53 out of the 59 GLA variants tested in the non-GLP assay matched the GLP-HEK amenability classification. Considering the non-GLP assay was done without identical procedures and validated quality standards as in the GLP-HEK assay, differences in results are expected. We noted at least two deviations from the GLP-HEK assay that likely account for the discrepancies reported for 6 variants. First, the GLP-HEK assay uses qPCR to directly measure the amount of transfected plasmid DNA for transfection efficiency control. The method employed by Oommen et al., an indirect measurement of co-transfected, secreted embryonic alkaline phosphatase (SEAP), may be inaccurate because overexpression of mutant α-galactosidase A (α-Gal A) can affect trafficking and secretion of SEAP. Second, Oommen et al. used the relative activity (% of wild type) instead of absolute activity (nmol/mg/h) to calculate the fold-increase in α-Gal A activity in response to migalastat, causing values for 4 variants to narrowly miss the amenability criteria . . . In conclusion, the concern over assay variability seems unfounded, since amenability to migalastat is determined in a single GLP-certified laboratory. We believe physicians can have a high level of confidence in the approved GLP-HEK assay, which identifies GLA variants with the potential to respond to migalastat. Of course, individual response will need to be assessed clinically. (Excerpts from text, p. 1.)

Scheeren, T. W. L. and M. A. E. Ramsay (2019). “New Developments in Hemodynamic Monitoring.” J Cardiothorac Vasc Anesth 33 Suppl 1: S67-s72.

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Hemodynamic monitoring is an essential part of the perioperative management of the cardiovascular patient. It helps to detect hemodynamic alterations, diagnose their underlying causes, and optimize oxygen delivery to the tissues. Furthermore, hemodynamic monitoring is necessary to evaluate the adequacy of therapeutic interventions such as volume expansion or vasoactive medications. Recent developments include the move from static to dynamic variables to assess conditions such as cardiac preload and fluid responsiveness and the transition to less-invasive or even noninvasive monitoring techniques, at least in the perioperative setting. This review describes the available techniques that currently are being used in the care of the cardiovascular patient and discusses their strengths and limitations. Even though the thermodilution method remains the gold standard for measuring cardiac output (CO), the use of the pulmonary artery catheter has declined over the last decades, even in the setting of cardiovascular anesthesia. The transpulmonary thermodilution method, in addition to accurately measuring CO, provides the user with some additional helpful variables, of which extravascular lung water is probably the most interesting. Less-invasive monitoring techniques use, for example, pulse contour analysis to originate flow-derived variables such as stroke volume and CO from the arterial pressure signal, or they may measure the velocity-time integral in the descending aorta to estimate the stroke volume, using, for example, the esophageal Doppler. Completely noninvasive methods such as the volume clamp method use finger cuffs to reconstruct the arterial pressure waveform, from which stroke volume and CO are calculated. All of these less-invasive CO monitoring devices have percentage errors around 40% compared with reference methods (thermodilution), meaning that the values are not interchangeable.